I spoke with Dr. Steg soon after he lambasted the FDA-mandated cardiovascular safety trials at ESC, and he further explained to me that while he didn’t dispute the importance of better evaluating the cardiovascular safety of these oral hypoglycemic drugs, he believed this could be more efficiently assessed with a more comprehensive approach to postmarketing surveillance. He also highlighted the importance of examining cardiovascular safety in type 2 diabetes patients who better resemble real-world patients instead of in the extreme high-risk patients who have enrolled in the trials. Finally, Dr. Steg told me that he wasn’t nearly as skeptical of these trials when the FDA first announced its guidance 7 years ago, but grew increasingly dismayed as he saw how the laudable goal of collecting data on cardiovascular safety led to such profligate and questionable studies.
Attitudes shifted dramatically fewer than 3 weeks later at EASD when the empagliflozin results came out from the EMPA-REG OUTCOME study. Randomizing 7,028 patients, the study showed that treatment with either of two dosages of empagliflozin, a blocker of the sodium glucose cotransporter 2 (SGLT-2) protein in the kidney, on top of standard oral hypoglycemic and other standard lipid-lowering and antihypertensive therapies produced a “wonderful and quite profound” 38% relative risk reduction in the rate of cardiovascular death, a 32% drop in all-cause death, and a 35% cut in heart failure hospitalizations, noted trial discussant Dr. Hertzel C. Gerstein. The “unexpected” results “will open new research,” Dr. Gerstein added when speaking at EASD. “The claims that people have made that large, randomized clinical trials in patients with diabetes are not needed appear unfounded. Here is a perfect case; we need to do these trials to find lifesaving therapies.”
The empagliflozin results were so dramatic and surprising that you can’t help wondering what would have happened if the FDA had not issued its mandate for cardiovascular safety studies in 2008. Would a trial like EMPA-REG OUTCOME ever have been done? Would this effect, which the researchers suggested was likely a class effect for all SGLT-2 inhibitors, ever have been found?
The empagliflozin findings also raise doubts about the unwavering reliance cardiovascular studies have had on a primary combined outcome that marries patient survival with the incidence of nonfatal ischemic events, strokes, and MIs. The EMPA-REG OUTCOME showed a major survival benefit while simultaneously having no discernible impact on nonfatal ischemic events.
The question of what aside from the FDA’s mandate might have gotten a trial like EMPA-REG OUTCOME off the ground is especially important because the findings hint that SGLT-2 inhibitors may have treatment implications that go beyond patients with type 2 diabetes. The rapid onset of the mortality benefit seemed to point to the diuretic effect of the drug as a major mediating factor, said several at the EASD session. Might SGLT-2 inhibitors be the eagerly sought new option for managing fluid congestion in the organs of patients with acute heart failure? Aside from survival it was heart failure hospitalization where the treatment showed benefit. Better fluid management is currently a desperate need as heart failure physicians increasingly recognize that diuretic treatment alone often is inadequate for purging excess fluid from affected organs in patients with acute heart failure episodes.
Some critics of the FDA mandate weren’t willing to accept that it made EMPA-REG OUTCOME possible. A New York Times news article published on September 18 quoted Dr. Robert E. Ratner from the American Diabetes Association as saying that studies like EMPA-REG OUTCOME get launched through the initiative of drug companies acting on their own, without FDA prodding. Perhaps Dr. Ratner is correct, but which studies out there now reflect this? It certainly doesn’t seem like companies have been motivated to organize trials that assess the cardiovascular impact of oral hypoglycemic drugs outside of meeting the FDA’s requirements.
A comment that nicely summed up the game-changing impact of the empagliflozin study came from a member of the EASD audience in Stockholm, the last attendee to pose a comment from the floor as the session wrapped up on Sept. 17. “I hope everyone in the audience understands what has happened, how important this is, a real landmark study,” commented Dr. Klas Malmberg, a cardiologist and diabetes researcher at the Karolinska Institute in Stockholm.
This unexpected finding from a large outcomes study looks like it may substantially alter the way type 2 diabetes and perhaps other diseases will get treated in the future. The finding also singlehandedly morphed the FDA’s safety study mandate from “a waste of resources” to the heroic driver behind a landmark study.
